Project Summary/Abstract This proposal presents a five-year research career development plan with a focus on the study of an immunomodulatory surface receptor Leukocyte immunoglobulin-like receptor subfamily B4 (LILRB4) and its role in acute myeloid leukemia (AML). The candidate is currently an Assistant Instructor at the University of Texas Southwestern Medical Center in the department of Pathology, division of Blood Banking and Transfusion Medicine. The outlined proposal builds on the candidate?s previous research and clinical experience in cancer immunology by integrating new domains of expertise by primary mentor, Dr. Alec Zhang: immunomodulatory surface immunoreceptor tyrosine-based inhibitory motif (ITIM) containing receptors and AML. The candidate expects to develop interdisciplinary skills from didactic activities and proposed experiments to make a successful transition to an independent physician scientist with an expertise in the immune modulation of hematologic malignancies. AML is one of the most common leukemia in adult that account for about 1.3% of new cancer cases in the US. Prognosis of AML remains poor despite therapy, partly due to the gaps in understanding the immunomodulation in AML. The candidate recently reported the role of LILRB4, a member of ITIM containing immunomodulatory receptor, in AML pathophysiology by suppressing T cell immune response and promoting migration of AML cells. In addition to the functional roles, the candidate also helped identify a hitherto unknown ligand of LILRB4 (Apolipoprotein E) and down-stream signaling pathways involving SHP-2 and uPAR/Arginase. However, preliminary data suggest that the activation and signal transduction of LILRB4 is unlikely a simple, linear event but rather involve multiple molecules. In addition to Apolipoprotein E, CD166 has been reported as a ligand of LILRB4. Also, preliminary data suggest the role of STAT3 and CCL3 in the T cell suppression and AML cell migration mediated by LILRB4. This project aims to identify the signaling molecules contributing to LILRB4 signal in AML and clarify their functional significance. As such, the aims of this proposal are 1) Study the role of interaction between apolipoprotein E and CD166 on LILRB4 activation, 2) Determine the cytoplasmic mediators of LILRB4 signaling responsible for the infiltration of leukemia cells and inhibition of T cell immunity, and 3) Identify the downstream targets of LILRB4 signaling in leukemia development. Upon successful completion, the scientific objectives of this proposal are expected to deepen our understanding of the role of LILRB4 in AML with potential implications for better understanding the signaling pathways of other ITIM containing immune modulatory receptors.